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Infection Defense May Spur Alzheimer’s

For years, a prevailing theory has been that one of the chief villains in Alzheimer’s disease has no real function other than as a waste product that the brain never properly disposed of.

The material, a protein called beta amyloid, or A-beta, piles up into tough plaques that destroy signals between nerves. When that happens, people lose their memory, their personality changes and they stop recognizing friends and family.

But now researchers at Harvard suggest that the protein has a real and unexpected function — it may be part of the brain’s normal defenses against invading bacteria and other microbes.

Other Alzheimer’s researchers say the findings, reported in the current issue of the journal PLoS One, are intriguing, though it is not clear whether they will lead to new ways of preventing or treating the disease.

The new hypothesis got its start late one Friday evening in the summer of 2007 in a laboratory at Harvard Medical School. The lead researcher, Rudolph E. Tanzi, a neurology professor who is also director of the genetics and aging unit at Massachusetts General Hospital, said he had been looking at a list of genes that seemed to be associated with Alzheimer’s disease.

To his surprise, many looked just like genes associated with the so-called innate immune system, a set of proteins the body uses to fight infections. The system is particularly important in the brain, because antibodies cannot get through the blood-brain barrier, the membrane that protects the brain. When the brain is infected, it relies on the innate immune system to protect it.

That evening, after the lab’s usual end-of-the-week beer hour, Dr. Tanzi wandered into the office of a junior faculty member, Robert D. Moir, and mentioned what he had seen. As Dr. Tanzi recalled, Dr. Moir turned to him and said, “Yeah, well, look at this.”

He handed Dr. Tanzi a spreadsheet. It was a comparison of A-beta and a well-known protein of the innate immune system, LL-37. The likenesses were uncanny.

Among other things, the two proteins had similar structures. And like A-beta, LL-37 tends to clump into hard little balls.

In rodents, the protein that corresponds to LL-37 protects against brain infections. People who make low levels of LL-37 are at increased risk of serious infections and have higher levels of atherosclerotic plaques, arterial growths that impede blood flow.

The scientists could hardly wait to see if A-beta, like LL-37, killed microbes. They mixed A-beta with microbes that LL-37 is known to kill — listeria, staphylococcus, pseudomonas. It killed 8 out of 12.

“We did the assays exactly as they have been done for years,” Dr. Tanzi said. “And A-beta was as potent or, in some cases, more potent than LL-37.”

Then the investigators exposed the yeast Candida albicans, a major cause of meningitis, to tissue from the hippocampal regions of brains from people who had died of Alzheimer’s and from people of the same age who did not have dementia when they died.

Photo

COMMON VILLAIN Bacteria being attacked by beta amyloid, in this image enlarged 18,500 times.Credit
Lee Goldstein, Robert Moir, Rudy Tanzi

Brain samples from Alzheimer’s patients were 24 percent more active in killing the yeast. But if the samples were first treated with an antibody that blocked A-beta, they were no better than brain tissue from nondemented people in killing the yeast.

The innate immune system is also set in motion by traumatic brain injuries and strokes and by atherosclerosis that causes reduced blood flow to the brain, Dr. Tanzi noted.

And the system is spurred by inflammation. It is known that patients with Alzheimer’s disease have inflamed brains, but it has not been clear whether A-beta accumulation was a cause or an effect of the inflammation. Perhaps, Dr. Tanzi said, A-beta levels rise as a result of the innate immune system’s response to inflammation; it may be a way the brain responds to a perceived infection.

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But does that mean Alzheimer’s disease is caused by an overly exuberant brain response to an infection?

That’s one possible reason, along with responses to injuries and inflammation and the effects of genes that cause A-beta levels to be higher than normal, Dr. Tanzi said. However, some researchers say that all the pieces of the A-beta innate immune systems hypothesis are not in place.

Dr. Norman Relkin, director of the memory disorders program at NewYork-Presbyterian/Weill Cornell hospital, said that although the idea was “unquestionably fascinating,” the evidence for it was “a bit tenuous.”

As for the link with infections, Dr. Steven T. DeKosky, an Alzheimer’s researcher who is vice president and dean of the University of Virginia School of Medicine, noted that scientists have long looked for evidence linking infections to Alzheimer’s and have come up mostly empty-handed.

But if Dr. Tanzi is correct about A-beta being part of the innate immune system, that would raise questions about the search for treatments to eliminate the protein from the brain.

“It means you don’t want to hit A-beta with a sledgehammer,” Dr. Tanzi said. “It says what we need is the equivalent of a statin for the brain so you can dial it down but not turn it off.” (Dr. Tanzi is a co-founder of two companies, Prana Biotechnology and Neurogenetic Pharmaceutical, that are trying to dial down A-beta.)

Dr. Relkin said that even if A-beta were not part of the innate immune system, it might not be a good idea to remove it all, along with the hard balls of plaque it makes in the brain.

In the past, Dr. Relkin said, scientists assumed “that the pathology was the plaque.” Now, he likens removing plaque to digging up bullets at the Gettysburg battlefield.

The more bullets in an area, the more intense the fighting was. But “digging up bullets will not change the outcome of the battle,” he said. “Most of us don’t believe that removing plaque from the brain is the end-all.”

But other scientists not connected with the discovery said they were impressed by the new findings.

“It changes our thinking about Alzheimer’s disease,” said Dr. Eliezer Masliah, who heads the experimental neuropathology laboratory at the University of California, San Diego. “I don’t think we ever thought about that possibility for A-beta.”

Dr. Masliah is intrigued by the idea that aggregates of A-beta may be killing bacteria and brain cells by the same mechanism. He noted that Dr. Tanzi had a track record of coming up with unusual ideas about Alzheimer’s disease that later turn out to be correct.

“I think he’s onto something important,” Dr. Masliah said.

Correction: March 15, 2010

An article on Tuesday about new research on Alzheimer’s disease referred incorrectly to a substance used in an experiment to determine whether the protein beta amyloid  a chief villain in Alzheimer’s  also had a role in fighting infection. As noted in the article’s previous sentence, the substance, Candida albicans, is a yeast, not a bacterium.

A version of this article appears in print on March 9, 2010, on Page D5 of the New York edition with the headline: Infection Defense May Spur Alzheimer’s. Order Reprints|Today's Paper|Subscribe